{"gene":"PACS2","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2005,"finding":"PACS-2 controls the apposition of mitochondria with the ER; depletion of PACS-2 causes BAP31-dependent mitochondria fragmentation and uncoupling from the ER. PACS-2 also translocates Bid to mitochondria in response to apoptotic inducers, triggering truncated Bid formation, cytochrome c release, and caspase-3 activation.","method":"siRNA knockdown, subcellular fractionation, fluorescence microscopy, co-immunoprecipitation, cell death assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in a highly-cited foundational paper; replicated by subsequent work","pmids":["15692567"],"is_preprint":false},{"year":2008,"finding":"PACS-2 interacts with calnexin's cytosolic domain to sort calnexin between the rough ER, mitochondria-associated membrane (MAM), and plasma membrane. Phosphorylation of calnexin Ser554/564 by CK2 reduces its binding to PACS-2, redirecting calnexin to the cell surface.","method":"siRNA knockdown, co-immunoprecipitation, phosphomimetic mutagenesis, immunofluorescence, flow cytometry","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal pulldowns plus mutagenesis and multiple readouts in one study","pmids":["18417615"],"is_preprint":false},{"year":2008,"finding":"HIV-1 Nef binds PACS-2 via Nef EEEE65, which targets Nef to the paranuclear/TGN region, enabling PXXP75 to activate a TGN-localized Src family kinase (SFK)–ZAP70–PI3K cascade required for MHC-I down-regulation. Genetic loss of PACS-2 (Pacs-2−/− splenocytes and fibroblasts) prevents Nef paranuclear localization and MHC-I internalization.","method":"Co-immunoprecipitation, siRNA knockdown, Pacs-2 knockout mouse cells, fluorescence microscopy, kinase assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic KO confirms siRNA result; multiple orthogonal methods","pmids":["18296443"],"is_preprint":false},{"year":2009,"finding":"PACS-2 is phosphorylated at Ser437 in vivo by Akt; phospho-Ser437 binds 14-3-3 with high affinity, which represses PACS-2 apoptotic activity while maintaining its membrane-trafficking function. TRAIL triggers Ser437 dephosphorylation, switching PACS-2 from a homeostatic to a pro-apoptotic state.","method":"In vivo phosphorylation mapping, pharmacological Akt inhibition, genetic Akt studies, 14-3-3 co-immunoprecipitation, TRAIL cytotoxicity assays, mouse hepatocyte infection model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — phosphosite identification combined with genetic and pharmacological validation, in vivo model","pmids":["19481529"],"is_preprint":false},{"year":2012,"finding":"PACS-2 and PACS-1 interact with Nef via a bipartite site formed by Nef EEEE65 (N-terminal domain) and W113 (core domain) binding to a cargo subsite on PACS-1/PACS-2. This interaction occurs on Rab5- and Rab7-positive endosomes (visualized by bimolecular fluorescence complementation) and is required for Nef-induced MHC-I down-regulation.","method":"Bimolecular fluorescence complementation, co-immunoprecipitation, site-directed mutagenesis, MHC-I surface assay in PBMCs","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of interaction sites plus live-cell imaging and functional readout","pmids":["22496420"],"is_preprint":false},{"year":2012,"finding":"TRAIL induces recruitment of PACS-2 to DR5-positive endosomes where it forms a complex with Bim and Bax on lysosomal membranes, promoting lysosomal membrane permeabilization and cathepsin B release. In vitro, recombinant PACS-2 binds Bim directly but not Bax; Bim is required for subsequent Bax recruitment.","method":"shRNA knockdown, co-immunoprecipitation, in vitro binding assay with recombinant proteins, lysosomal membrane permeabilization assay, clonogenic survival","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution of direct binding plus cellular knockdown with defined pathway placement","pmids":["22645134"],"is_preprint":false},{"year":2014,"finding":"PACS-2 shuttles from the cytoplasm to the nucleus where it interacts with SIRT1 and directly inhibits SIRT1-catalyzed p53 deacetylation, thereby sustaining p53 acetylation and p21 induction required for DNA-damage-induced cell-cycle arrest. Pacs-2−/− thymocytes show reduced p53 acetylation and blunted p21 induction.","method":"In vitro SIRT1 deacetylation assay, co-immunoprecipitation, Pacs-2 knockout mouse thymocytes, SIRT1 inhibitor rescue, subcellular fractionation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay plus genetic KO validation","pmids":["25159152"],"is_preprint":false},{"year":2014,"finding":"cIAP-1 and cIAP-2 directly bind PACS-2 and mediate K48-linked poly-ubiquitination of PACS-2, targeting it for proteasomal degradation. Dual cIAP knockout reduces PACS-2 ubiquitination, elevates PACS-2 levels, and sensitizes cells to TRAIL-induced lysosomal membrane permeabilization in a PACS-2-dependent manner.","method":"Cell-free ubiquitination assay, co-immunoprecipitation, single and double c-Iap knockout mouse hepatocytes, cycloheximide chase","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — cell-free ubiquitination reconstitution plus genetic KO confirmation","pmids":["24633224"],"is_preprint":false},{"year":2015,"finding":"PACS-2 co-localizes with ADAM17 on early endosomes and is required for recycling of internalized ADAM17 away from degradative pathways back to the cell surface. PACS-2 loss reduces ADAM17 cell-surface levels, ADAM17-dependent ErbB ligand shedding, and EGFR signaling; Pacs2−/− mice show reduced phospho-EGFR and intestinal proliferation.","method":"Genome-wide siRNA screen, confocal co-localization, ADAM17 recycling assay, Pacs2 knockout mice, EGFR phosphorylation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — unbiased genome-wide screen hit validated with KO mice and multiple cellular assays","pmids":["26108729"],"is_preprint":false},{"year":2016,"finding":"Cytoplasmic PACS-2 interacts with ATM to drive NF-κB activation and induction of anti-apoptotic Bcl-xL following DNA damage. Pacs-2−/− thymocytes show blunted Bcl-xL induction, increased mitochondrial outer membrane permeabilization, and accelerated apoptosis after genotoxic stress; PACS-2 is not required for TNFα-induced NF-κB activation.","method":"Co-immunoprecipitation, Pacs-2 knockout mouse thymocytes, mitochondrial membrane permeabilization assay, NF-κB reporter, western blot","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple pathway readouts; selectivity control for TNFα pathway","pmids":["26943323"],"is_preprint":false},{"year":2018,"finding":"PACS-2 engages an insulin-responsive sensor in the SIRT1 N-terminal disordered region comprising an acidic cluster (AC) and a 3-helix bundle (3HB). DBC1 removes a distal shield from the 3HB, permitting PACS-2 to engage the AC and transiently exposed helix 3, disrupting 3HB structure and inhibiting SIRT1 catalysis. The SIRT1 activator SRT1720 stabilizes the 3HB and protects SIRT1 from PACS-2-mediated inhibition.","method":"NMR structural analysis, in vitro SIRT1 deacetylation assay, co-immunoprecipitation, mutagenesis, STAC binding assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — NMR structure combined with in vitro enzymatic assay and mutagenesis","pmids":["30415949"],"is_preprint":false},{"year":2018,"finding":"The recurrent PACS-2 E209K missense variant reduces the ability of the autoregulatory domain to modulate the interaction between the PACS-2 FBR (cargo-binding region) and client proteins, potentially disturbing cellular trafficking and causing developmental epileptic encephalopathy.","method":"Functional binding assay comparing WT and E209K FBR-client interactions, whole-exome sequencing in 14 individuals","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — single functional assay supporting mechanistic inference; replicated clinically across 14 cases","pmids":["29656858"],"is_preprint":false},{"year":2019,"finding":"PACS-2 knockdown impairs mitophagosome formation and mitophagy in vascular smooth muscle cells; increased MAM contacts and PACS-2-associated MAMs are observed upon atherogenic lipid stimulation, and disrupting MAMs via PACS-2 loss potentiates VSMC apoptosis.","method":"High-resolution confocal microscopy, proximity ligation assay, siRNA knockdown, mitophagy flux assay, apoptosis assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple imaging methods with functional readout in single lab","pmids":["31242668"],"is_preprint":false},{"year":2019,"finding":"PACS2 promotes MAM formation and mitochondrial Ca2+ transfer in endothelial cells; ox-LDL increases PACS2 localization at mitochondria and ER-mitochondria contacts, and silencing PACS2 inhibits ox-LDL-induced mitochondrial Ca2+ elevation, ROS production, MMP loss, cytochrome c release, and apoptosis.","method":"siRNA knockdown, confocal microscopy of MAM contacts, mitochondrial Ca2+ measurement, ROS/MMP/cytochrome c assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple functional readouts but single lab","pmids":["30970236"],"is_preprint":false},{"year":2022,"finding":"PACS-2 interacts with BECN1 (Beclin-1) and mediates its relocalization to MAM, where BECN1 promotes mitophagosome formation. PACS-2 overexpression blocks mitochondrial DRP1 recruitment, reducing excessive mitochondrial fission and restoring mitophagy in high-glucose conditions.","method":"Co-immunoprecipitation, proximity ligation assay, confocal microscopy, conditional Pacs-2 knockout mice, PACS-2 overexpression in HK-2 cells, mitophagy flux assay","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus conditional KO mouse model plus multiple cellular assays","pmids":["35133431"],"is_preprint":false},{"year":2022,"finding":"PACS2 interacts with TRPV1; reduced PACS2 levels during ER stress are influenced by this interaction, and restoration of PACS2 via TRPV1-modulating drug capsaicin reduces ER-mitochondria uncoupling and alveolar epithelial apoptosis in IPF models.","method":"Co-immunoprecipitation, confocal microscopy, overexpression/knockdown in AEC2 cells, precision-cut lung slices from IPF patients, apoptosis assay","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP evidence of PACS2-TRPV1 interaction with functional pharmacological rescue; single lab","pmids":["35212819"],"is_preprint":false},{"year":2022,"finding":"PACS-2 E209K mutation increases the protein's half-life (slower turnover), increases association with 14-3-3ε, and increases susceptibility to staurosporine-induced apoptosis compared to wild-type PACS-2.","method":"Cycloheximide chase, co-immunoprecipitation, staurosporine apoptosis assay in HCT116 cells","journal":"ACS omega","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple biochemical assays in single lab characterizing mutant behavior","pmids":["36188273"],"is_preprint":false},{"year":2023,"finding":"PACS-2 interacts with transcription factor EB (TFEB) and promotes its nuclear translocation, which activates expression of the ER-phagy receptor FAM134B, thereby facilitating ER-phagy in renal tubular cells.","method":"Co-immunoprecipitation, nuclear fractionation, PACS-2 overexpression and siRNA knockdown, FAM134B siRNA rescue, Pacs-2 proximal tubule-specific KO mice","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus conditional KO with defined pathway hierarchy; single lab","pmids":["37794057"],"is_preprint":false},{"year":2024,"finding":"PACS-2 suppresses phosphorylation and nuclear translocation of SP1, thereby downregulating LRRK2 expression. Reduced LRRK2 decreases ubiquitination and degradation of Mfn2 via the JNK pathway, preserving MAM integrity and nucleus pulposus stem cell survival.","method":"Co-immunoprecipitation, western blot, Pacs-2 knockout mice, overexpression studies, ubiquitination assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway hierarchy established with multiple protein interaction and KO data; single lab","pmids":["41190767"],"is_preprint":false},{"year":2024,"finding":"PACS-2 is required for CCHFV glycoprotein (Gn and Gc) trafficking through the retrograde network; loss of PACS-2 impairs CCHFV assembly and release of infectious viral particles.","method":"Infection assays, biochemical trafficking assays, confocal microscopy in virus-producing cells, siRNA knockdown","journal":"Emerging microbes & infections","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple assays (infection, biochemical, imaging) in single study","pmids":["38661085"],"is_preprint":false}],"current_model":"PACS-2 is a multifunctional cytosolic sorting protein that (1) tethers ER–mitochondria contact sites (MAMs) to regulate Ca2+ transfer, lipid synthesis, mitophagy, and ER-phagy; (2) traffics apoptotic effectors (Bid, Bim/Bax) and anti-apoptotic signals (Bcl-xL via ATM–NF-κB) in response to death ligands or DNA damage; (3) acts as a homeostatic/apoptotic switch toggled by Akt-mediated phosphorylation of Ser437 and 14-3-3 binding; (4) directly inhibits SIRT1 deacetylase activity by engaging a disordered N-terminal sensor, modulating the p53–p21 DNA-damage response; and (5) directs trafficking of membrane cargo including ADAM17, calnexin, and viral glycoproteins through TGN/endosomal recycling pathways."},"narrative":{"teleology":[],"mechanism_profile":null,"mechanistic_narrative":"Parse failed — see logs"},"prefetch_data":{"uniprot":{"accession":"Q86VP3","full_name":"Phosphofurin acidic cluster sorting protein 2","aliases":["PACS1-like protein"],"length_aa":889,"mass_kda":97.7,"function":"Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis. In addition, in response to apoptotic inducer, translocates BIB to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated BID, the release of cytochrome c, the activation of caspase-3 thereby causing cell death. May also be involved in ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments","subcellular_location":"Endoplasmic reticulum; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q86VP3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PACS2","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PACS2","total_profiled":1310},"omim":[{"mim_id":"618067","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 66; DEE66","url":"https://www.omim.org/entry/618067"},{"mim_id":"610423","title":"PHOSPHOFURIN ACIDIC CLUSTER SORTING PROTEIN 2; PACS2","url":"https://www.omim.org/entry/610423"},{"mim_id":"607492","title":"PHOSPHOFURIN ACIDIC CLUSTER SORTING PROTEIN 1; PACS1","url":"https://www.omim.org/entry/607492"},{"mim_id":"308350","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 1; DEE1","url":"https://www.omim.org/entry/308350"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":95.7},{"tissue":"skeletal muscle","ntpm":31.6}],"url":"https://www.proteinatlas.org/search/PACS2"},"hgnc":{"alias_symbol":["KIAA0602"],"prev_symbol":["PACS1L"]},"alphafold":{"accession":"Q86VP3","domains":[{"cath_id":"2.60.40.150","chopping":"23-179","consensus_level":"high","plddt":85.8853,"start":23,"end":179},{"cath_id":"-","chopping":"467-651","consensus_level":"high","plddt":91.363,"start":467,"end":651},{"cath_id":"2.60.200.40","chopping":"654-684_745-756_772-810_827-870","consensus_level":"medium","plddt":83.0145,"start":654,"end":870}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VP3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VP3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VP3-F1-predicted_aligned_error_v6.png","plddt_mean":66.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PACS2","jax_strain_url":"https://www.jax.org/strain/search?query=PACS2"},"sequence":{"accession":"Q86VP3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86VP3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86VP3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VP3"}},"corpus_meta":[{"pmid":"15692567","id":"PMC_15692567","title":"PACS-2 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cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/11274944","citation_count":65,"is_preprint":false},{"pmid":"30970236","id":"PMC_30970236","title":"PACS2 is required for ox-LDL-induced endothelial cell apoptosis by regulating mitochondria-associated ER membrane formation and mitochondrial Ca2+ elevation.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30970236","citation_count":58,"is_preprint":false},{"pmid":"29656858","id":"PMC_29656858","title":"A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29656858","citation_count":57,"is_preprint":false},{"pmid":"22496420","id":"PMC_22496420","title":"An interdomain binding site on HIV-1 Nef interacts with PACS-1 and PACS-2 on endosomes to down-regulate 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metalloproteinase ADAM17.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26108729","citation_count":45,"is_preprint":false},{"pmid":"30415949","id":"PMC_30415949","title":"An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30415949","citation_count":41,"is_preprint":false},{"pmid":"26943323","id":"PMC_26943323","title":"PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.","date":"2016","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/26943323","citation_count":30,"is_preprint":false},{"pmid":"39633391","id":"PMC_39633391","title":"PACS2/CPT1A/DHODH signaling promotes cardiomyocyte ferroptosis in diabetic cardiomyopathy.","date":"2024","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/39633391","citation_count":29,"is_preprint":false},{"pmid":"36481261","id":"PMC_36481261","title":"Ferulic acid attenuates high glucose-induced MAM alterations via PACS2/IP3R2/FUNDC1/VDAC1 pathway activating proapoptotic proteins and ameliorates cardiomyopathy in diabetic rats.","date":"2022","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/36481261","citation_count":27,"is_preprint":false},{"pmid":"24633224","id":"PMC_24633224","title":"Cellular inhibitor of apoptosis (cIAP)-mediated ubiquitination of phosphofurin acidic cluster sorting protein 2 (PACS-2) negatively regulates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24633224","citation_count":27,"is_preprint":false},{"pmid":"35212819","id":"PMC_35212819","title":"PACS2-TRPV1 axis is required for ER-mitochondrial tethering during ER stress and lung fibrosis.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35212819","citation_count":25,"is_preprint":false},{"pmid":"36138342","id":"PMC_36138342","title":"PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease.","date":"2022","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/36138342","citation_count":25,"is_preprint":false},{"pmid":"37794057","id":"PMC_37794057","title":"PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37794057","citation_count":22,"is_preprint":false},{"pmid":"30684285","id":"PMC_30684285","title":"Expanding the clinical spectrum associated with PACS2 mutations.","date":"2019","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30684285","citation_count":19,"is_preprint":false},{"pmid":"35865947","id":"PMC_35865947","title":"AKT/PACS2 Participates in Renal Vascular Hyperpermeability by Regulating Endothelial Fatty Acid Oxidation in Diabetic Mice.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35865947","citation_count":13,"is_preprint":false},{"pmid":"33369122","id":"PMC_33369122","title":"Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33369122","citation_count":11,"is_preprint":false},{"pmid":"36968068","id":"PMC_36968068","title":"Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36968068","citation_count":11,"is_preprint":false},{"pmid":"39173402","id":"PMC_39173402","title":"Renal denervation improves mitochondrial oxidative stress and cardiac hypertrophy through inactivating SP1/BACH1-PACS2 signaling.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39173402","citation_count":9,"is_preprint":false},{"pmid":"36188273","id":"PMC_36188273","title":"The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis.","date":"2022","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/36188273","citation_count":9,"is_preprint":false},{"pmid":"35770754","id":"PMC_35770754","title":"First reported case of an inherited PACS2 pathogenic variant with variable expression.","date":"2022","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/35770754","citation_count":7,"is_preprint":false},{"pmid":"31432119","id":"PMC_31432119","title":"MAP‑1B, PACS‑2 and AHCYL1 are regulated by miR‑34A/B/C and miR‑449 in neuroplasticity following traumatic spinal cord injury in rats: Preliminary explorative results from microarray data.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/31432119","citation_count":7,"is_preprint":false},{"pmid":"34405643","id":"PMC_34405643","title":"[Early infantile epileptic encephalopathy caused by PACS2 gene variation: three cases report and literature review].","date":"2021","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34405643","citation_count":6,"is_preprint":false},{"pmid":"40653022","id":"PMC_40653022","title":"PACS2 initiates foam cell formation in macrophages through the ROS-PPARγ-CD36 positive feedback loop.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40653022","citation_count":5,"is_preprint":false},{"pmid":"35951762","id":"PMC_35951762","title":"Knockdown of circ_0002194 protects against oxidized low-density lipoprotein-induced cell damage via the regulation of the miR-637/PACS2 axis in human vascular endothelial cells.","date":"2022","source":"Interactive cardiovascular and thoracic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/35951762","citation_count":5,"is_preprint":false},{"pmid":"29312533","id":"PMC_29312533","title":"Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29312533","citation_count":5,"is_preprint":false},{"pmid":"34894068","id":"PMC_34894068","title":"Vein of Galen aneurysm, dilated cardiomyopathy, and slender habitus in a patient with a recurrent pathogenic variant in PACS2.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34894068","citation_count":4,"is_preprint":false},{"pmid":"39031646","id":"PMC_39031646","title":"PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes.","date":"2024","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39031646","citation_count":4,"is_preprint":false},{"pmid":"40775117","id":"PMC_40775117","title":"PACS2/PKCα/NOX4 pathway damaged the renal vascular endothelial barrier by promoting ROS production in diabetic nephropathy mice.","date":"2025","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40775117","citation_count":3,"is_preprint":false},{"pmid":"37189870","id":"PMC_37189870","title":"Long-Term Outcome of Neonatal Seizure with PACS2 Mutation: Case Series and Literature Review.","date":"2023","source":"Children (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37189870","citation_count":3,"is_preprint":false},{"pmid":"37064331","id":"PMC_37064331","title":"First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations.","date":"2022","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/37064331","citation_count":2,"is_preprint":false},{"pmid":"41190767","id":"PMC_41190767","title":"PACS-2 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1/LRRK2/Mfn2 Axis.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41190767","citation_count":1,"is_preprint":false},{"pmid":"38545008","id":"PMC_38545008","title":"A missense variant in the PACS2 gene cause Epileptic Encephalopathy and seizures in Saudi family.","date":"2024","source":"Pakistan journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38545008","citation_count":1,"is_preprint":false},{"pmid":"40869285","id":"PMC_40869285","title":"AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40869285","citation_count":1,"is_preprint":false},{"pmid":"38031819","id":"PMC_38031819","title":"PACS2 pathogenic variant associated with malformation of cortical development and epilepsy.","date":"2023","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/38031819","citation_count":1,"is_preprint":false},{"pmid":"39911171","id":"PMC_39911171","title":"PACS2, PACS1, and VACTERL: A Clinical Overlap.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/39911171","citation_count":1,"is_preprint":false},{"pmid":"34625934","id":"PMC_34625934","title":"[Clinical and genetic analysis of PACS2 gene variant in two child patients with developmental and epileptic encephalopathy 66].","date":"2021","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34625934","citation_count":1,"is_preprint":false},{"pmid":"38540691","id":"PMC_38540691","title":"Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38540691","citation_count":0,"is_preprint":false},{"pmid":"39738582","id":"PMC_39738582","title":"Understanding PACS2 syndrome's pathomechanism by studying E209K and E211K mutations.","date":"2024","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/39738582","citation_count":0,"is_preprint":false},{"pmid":"41692703","id":"PMC_41692703","title":"Quercetin Alleviates Endothelial Dysfunction in Atherosclerosis by Inhibiting Ferroptosis Through PACS2/HMOX-1 Pathway.","date":"2026","source":"The American journal of Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41692703","citation_count":0,"is_preprint":false},{"pmid":"38712144","id":"PMC_38712144","title":"PACS-1 variant protein is aberrantly localized in C. elegans model of PACS1/PACS2 syndromes.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38712144","citation_count":0,"is_preprint":false},{"pmid":"41644764","id":"PMC_41644764","title":"MiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold Stress.","date":"2026","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/41644764","citation_count":0,"is_preprint":false},{"pmid":"38661085","id":"PMC_38661085","title":"The PACS-2 protein and trafficking motifs in CCHFV Gn and Gc cytoplasmic domains govern CCHFV assembly.","date":"2024","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/38661085","citation_count":0,"is_preprint":false},{"pmid":"41687826","id":"PMC_41687826","title":"PACS2 deficiency ameliorates hepatic steatosis via inhibition of the JNK signaling pathway in diabetic mice.","date":"2026","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41687826","citation_count":0,"is_preprint":false},{"pmid":"41962777","id":"PMC_41962777","title":"Crebanine attenuates copper neurotoxicity via PACS-2 upregulation and TXNIP/TRPV1 axis suppression.","date":"2026","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41962777","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29279,"output_tokens":4901,"usd":0.080676},"stage2":{"model":"claude-opus-4-6","input_tokens":8470,"output_tokens":1,"usd":0.063562},"total_usd":0.144238,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"PACS-2 controls the apposition of mitochondria with the ER; depletion of PACS-2 causes BAP31-dependent mitochondria fragmentation and uncoupling from the ER. PACS-2 also translocates Bid to mitochondria in response to apoptotic inducers, triggering truncated Bid formation, cytochrome c release, and caspase-3 activation.\",\n      \"method\": \"siRNA knockdown, subcellular fractionation, fluorescence microscopy, co-immunoprecipitation, cell death assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a highly-cited foundational paper; replicated by subsequent work\",\n      \"pmids\": [\"15692567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PACS-2 interacts with calnexin's cytosolic domain to sort calnexin between the rough ER, mitochondria-associated membrane (MAM), and plasma membrane. Phosphorylation of calnexin Ser554/564 by CK2 reduces its binding to PACS-2, redirecting calnexin to the cell surface.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, phosphomimetic mutagenesis, immunofluorescence, flow cytometry\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldowns plus mutagenesis and multiple readouts in one study\",\n      \"pmids\": [\"18417615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HIV-1 Nef binds PACS-2 via Nef EEEE65, which targets Nef to the paranuclear/TGN region, enabling PXXP75 to activate a TGN-localized Src family kinase (SFK)–ZAP70–PI3K cascade required for MHC-I down-regulation. Genetic loss of PACS-2 (Pacs-2−/− splenocytes and fibroblasts) prevents Nef paranuclear localization and MHC-I internalization.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Pacs-2 knockout mouse cells, fluorescence microscopy, kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO confirms siRNA result; multiple orthogonal methods\",\n      \"pmids\": [\"18296443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PACS-2 is phosphorylated at Ser437 in vivo by Akt; phospho-Ser437 binds 14-3-3 with high affinity, which represses PACS-2 apoptotic activity while maintaining its membrane-trafficking function. TRAIL triggers Ser437 dephosphorylation, switching PACS-2 from a homeostatic to a pro-apoptotic state.\",\n      \"method\": \"In vivo phosphorylation mapping, pharmacological Akt inhibition, genetic Akt studies, 14-3-3 co-immunoprecipitation, TRAIL cytotoxicity assays, mouse hepatocyte infection model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — phosphosite identification combined with genetic and pharmacological validation, in vivo model\",\n      \"pmids\": [\"19481529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PACS-2 and PACS-1 interact with Nef via a bipartite site formed by Nef EEEE65 (N-terminal domain) and W113 (core domain) binding to a cargo subsite on PACS-1/PACS-2. This interaction occurs on Rab5- and Rab7-positive endosomes (visualized by bimolecular fluorescence complementation) and is required for Nef-induced MHC-I down-regulation.\",\n      \"method\": \"Bimolecular fluorescence complementation, co-immunoprecipitation, site-directed mutagenesis, MHC-I surface assay in PBMCs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of interaction sites plus live-cell imaging and functional readout\",\n      \"pmids\": [\"22496420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRAIL induces recruitment of PACS-2 to DR5-positive endosomes where it forms a complex with Bim and Bax on lysosomal membranes, promoting lysosomal membrane permeabilization and cathepsin B release. In vitro, recombinant PACS-2 binds Bim directly but not Bax; Bim is required for subsequent Bax recruitment.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, in vitro binding assay with recombinant proteins, lysosomal membrane permeabilization assay, clonogenic survival\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution of direct binding plus cellular knockdown with defined pathway placement\",\n      \"pmids\": [\"22645134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PACS-2 shuttles from the cytoplasm to the nucleus where it interacts with SIRT1 and directly inhibits SIRT1-catalyzed p53 deacetylation, thereby sustaining p53 acetylation and p21 induction required for DNA-damage-induced cell-cycle arrest. Pacs-2−/− thymocytes show reduced p53 acetylation and blunted p21 induction.\",\n      \"method\": \"In vitro SIRT1 deacetylation assay, co-immunoprecipitation, Pacs-2 knockout mouse thymocytes, SIRT1 inhibitor rescue, subcellular fractionation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay plus genetic KO validation\",\n      \"pmids\": [\"25159152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"cIAP-1 and cIAP-2 directly bind PACS-2 and mediate K48-linked poly-ubiquitination of PACS-2, targeting it for proteasomal degradation. Dual cIAP knockout reduces PACS-2 ubiquitination, elevates PACS-2 levels, and sensitizes cells to TRAIL-induced lysosomal membrane permeabilization in a PACS-2-dependent manner.\",\n      \"method\": \"Cell-free ubiquitination assay, co-immunoprecipitation, single and double c-Iap knockout mouse hepatocytes, cycloheximide chase\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cell-free ubiquitination reconstitution plus genetic KO confirmation\",\n      \"pmids\": [\"24633224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PACS-2 co-localizes with ADAM17 on early endosomes and is required for recycling of internalized ADAM17 away from degradative pathways back to the cell surface. PACS-2 loss reduces ADAM17 cell-surface levels, ADAM17-dependent ErbB ligand shedding, and EGFR signaling; Pacs2−/− mice show reduced phospho-EGFR and intestinal proliferation.\",\n      \"method\": \"Genome-wide siRNA screen, confocal co-localization, ADAM17 recycling assay, Pacs2 knockout mice, EGFR phosphorylation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genome-wide screen hit validated with KO mice and multiple cellular assays\",\n      \"pmids\": [\"26108729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cytoplasmic PACS-2 interacts with ATM to drive NF-κB activation and induction of anti-apoptotic Bcl-xL following DNA damage. Pacs-2−/− thymocytes show blunted Bcl-xL induction, increased mitochondrial outer membrane permeabilization, and accelerated apoptosis after genotoxic stress; PACS-2 is not required for TNFα-induced NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, Pacs-2 knockout mouse thymocytes, mitochondrial membrane permeabilization assay, NF-κB reporter, western blot\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple pathway readouts; selectivity control for TNFα pathway\",\n      \"pmids\": [\"26943323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PACS-2 engages an insulin-responsive sensor in the SIRT1 N-terminal disordered region comprising an acidic cluster (AC) and a 3-helix bundle (3HB). DBC1 removes a distal shield from the 3HB, permitting PACS-2 to engage the AC and transiently exposed helix 3, disrupting 3HB structure and inhibiting SIRT1 catalysis. The SIRT1 activator SRT1720 stabilizes the 3HB and protects SIRT1 from PACS-2-mediated inhibition.\",\n      \"method\": \"NMR structural analysis, in vitro SIRT1 deacetylation assay, co-immunoprecipitation, mutagenesis, STAC binding assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure combined with in vitro enzymatic assay and mutagenesis\",\n      \"pmids\": [\"30415949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The recurrent PACS-2 E209K missense variant reduces the ability of the autoregulatory domain to modulate the interaction between the PACS-2 FBR (cargo-binding region) and client proteins, potentially disturbing cellular trafficking and causing developmental epileptic encephalopathy.\",\n      \"method\": \"Functional binding assay comparing WT and E209K FBR-client interactions, whole-exome sequencing in 14 individuals\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single functional assay supporting mechanistic inference; replicated clinically across 14 cases\",\n      \"pmids\": [\"29656858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PACS-2 knockdown impairs mitophagosome formation and mitophagy in vascular smooth muscle cells; increased MAM contacts and PACS-2-associated MAMs are observed upon atherogenic lipid stimulation, and disrupting MAMs via PACS-2 loss potentiates VSMC apoptosis.\",\n      \"method\": \"High-resolution confocal microscopy, proximity ligation assay, siRNA knockdown, mitophagy flux assay, apoptosis assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple imaging methods with functional readout in single lab\",\n      \"pmids\": [\"31242668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PACS2 promotes MAM formation and mitochondrial Ca2+ transfer in endothelial cells; ox-LDL increases PACS2 localization at mitochondria and ER-mitochondria contacts, and silencing PACS2 inhibits ox-LDL-induced mitochondrial Ca2+ elevation, ROS production, MMP loss, cytochrome c release, and apoptosis.\",\n      \"method\": \"siRNA knockdown, confocal microscopy of MAM contacts, mitochondrial Ca2+ measurement, ROS/MMP/cytochrome c assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple functional readouts but single lab\",\n      \"pmids\": [\"30970236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PACS-2 interacts with BECN1 (Beclin-1) and mediates its relocalization to MAM, where BECN1 promotes mitophagosome formation. PACS-2 overexpression blocks mitochondrial DRP1 recruitment, reducing excessive mitochondrial fission and restoring mitophagy in high-glucose conditions.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, confocal microscopy, conditional Pacs-2 knockout mice, PACS-2 overexpression in HK-2 cells, mitophagy flux assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus conditional KO mouse model plus multiple cellular assays\",\n      \"pmids\": [\"35133431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PACS2 interacts with TRPV1; reduced PACS2 levels during ER stress are influenced by this interaction, and restoration of PACS2 via TRPV1-modulating drug capsaicin reduces ER-mitochondria uncoupling and alveolar epithelial apoptosis in IPF models.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, overexpression/knockdown in AEC2 cells, precision-cut lung slices from IPF patients, apoptosis assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP evidence of PACS2-TRPV1 interaction with functional pharmacological rescue; single lab\",\n      \"pmids\": [\"35212819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PACS-2 E209K mutation increases the protein's half-life (slower turnover), increases association with 14-3-3ε, and increases susceptibility to staurosporine-induced apoptosis compared to wild-type PACS-2.\",\n      \"method\": \"Cycloheximide chase, co-immunoprecipitation, staurosporine apoptosis assay in HCT116 cells\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple biochemical assays in single lab characterizing mutant behavior\",\n      \"pmids\": [\"36188273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PACS-2 interacts with transcription factor EB (TFEB) and promotes its nuclear translocation, which activates expression of the ER-phagy receptor FAM134B, thereby facilitating ER-phagy in renal tubular cells.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, PACS-2 overexpression and siRNA knockdown, FAM134B siRNA rescue, Pacs-2 proximal tubule-specific KO mice\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus conditional KO with defined pathway hierarchy; single lab\",\n      \"pmids\": [\"37794057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PACS-2 suppresses phosphorylation and nuclear translocation of SP1, thereby downregulating LRRK2 expression. Reduced LRRK2 decreases ubiquitination and degradation of Mfn2 via the JNK pathway, preserving MAM integrity and nucleus pulposus stem cell survival.\",\n      \"method\": \"Co-immunoprecipitation, western blot, Pacs-2 knockout mice, overexpression studies, ubiquitination assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway hierarchy established with multiple protein interaction and KO data; single lab\",\n      \"pmids\": [\"41190767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PACS-2 is required for CCHFV glycoprotein (Gn and Gc) trafficking through the retrograde network; loss of PACS-2 impairs CCHFV assembly and release of infectious viral particles.\",\n      \"method\": \"Infection assays, biochemical trafficking assays, confocal microscopy in virus-producing cells, siRNA knockdown\",\n      \"journal\": \"Emerging microbes & infections\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple assays (infection, biochemical, imaging) in single study\",\n      \"pmids\": [\"38661085\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PACS-2 is a multifunctional cytosolic sorting protein that (1) tethers ER–mitochondria contact sites (MAMs) to regulate Ca2+ transfer, lipid synthesis, mitophagy, and ER-phagy; (2) traffics apoptotic effectors (Bid, Bim/Bax) and anti-apoptotic signals (Bcl-xL via ATM–NF-κB) in response to death ligands or DNA damage; (3) acts as a homeostatic/apoptotic switch toggled by Akt-mediated phosphorylation of Ser437 and 14-3-3 binding; (4) directly inhibits SIRT1 deacetylase activity by engaging a disordered N-terminal sensor, modulating the p53–p21 DNA-damage response; and (5) directs trafficking of membrane cargo including ADAM17, calnexin, and viral glycoproteins through TGN/endosomal recycling pathways.\"\n}\n```","stage2_raw":""}